MED221: Therapeutic Use Exemptions Notes

Therapeutic Use Exemptions (TUEs)

Learning Outcomes

  • Define TUEs and how they are applied.

  • Outline medical conditions where performance-enhancing drugs might be prescribed.

  • Explain the mechanism of action of beta-agonists and corticosteroids.

  • Outline evidence that beta-agonists can increase muscle hypertrophy and strength.

  • Outline evidence that corticosteroids can boost endurance exercise performance.

What is a Therapeutic Use Exemption (TUE)?

  • Athletes may have illnesses or conditions requiring medication.

  • If the medication is on the WADA Prohibited list, a TUE authorizes the athlete to take it.

  • Athletes are not automatically granted a TUE; they must follow the process for their sport, competition level, and national anti-doping agency.

Examples of TUEs

  • Insulin for type I diabetes.

  • Beta-2 agonist inhalers (e.g., salbutamol) for asthma.

  • Adderall for Attention Deficit Hyperactivity Disorder (ADHD).

Approval Criteria for TUE Applications

  • Significant impairment to health if the prohibited substance is withheld.

  • No additional performance enhancement; the substance should return the athlete to "normal."

  • No reasonable alternative treatments, or these treatments are ineffective.

How to Obtain a TUE

  • Athlete completes a TUE application form.

  • The application is reviewed, typically within 21 days.

  • Additional investigations may be requested, and the athlete is responsible for providing them.

  • Athletes typically make an annual declaration for chronic medical conditions.

Level of Competition

  • National level: Approved by the National Anti-Doping Agency (e.g., UKADA).

  • International level: Athlete included in the Registered Testing Pool (RTP).

  • National-level TUE may be reviewed when included in the RTP.

  • Athletes can confirm with UKADA or the International Testing Agency (ITA).

Retroactive TUEs

  • Granted for emergency treatment or acute medical condition.

  • Insufficient time to apply for a TUE in advance.

  • Specific rules or WADA may require/permit a retroactive TUE.

  • Issue: Potential for abuse by not applying for TUEs in advance.

Issues with TUEs

  • Potential exploitation of the TUE process.

    • Finding a doctor willing to write a prescription for a medicine that isn’t required.

    • Faking illness.

    • Faking diagnostic test results.

  • 51% of athletes believe others are using unnecessary TUEs (Overbye & Wagner, 2013).

Letter vs. Spirit of the Law

  • Letter of the law avoids punishment.

  • (Breaking) the spirit of the law gives a competitive edge (Dimeo & Moller, 2017).

TUE System Abuse

  • Adderall is a common TUE with potential performance-enhancing effects.

  • Cycling is frequently associated with corticosteroids and beta-2 agonists (e.g., Wiggins, Froome).

TUEs in Elite Sport

  • TUEs are allowed for ADHD and narcolepsy.

  • Use of dexamphetamine, methylphenidate, or modafinil (so-called "smart drugs") - Stimulants (Fitch, 2012).

Beta-Blockers

  • Mainly used for treatment of cardiac conditions.

  • Only necessary for sports that prohibit them.

  • Rarely granted for use during shooting (Fitch, 2012).

Diuretics

  • Used in the treatment of polycystic ovary syndrome (PCOS) and hypertension.

  • Renal disorders sometimes require diuretic use.

  • A TUE should never be granted for an athlete in a sport with weight categories (Fitch, 2012).

Blood Doping

  • No TUE for blood doping can be approved.

  • EPO (Erythropoietin) allowed for major renal disease.

  • Haemoglobin must never exceed 140g/L in males or 130g/L in females (Fitch, 2012).

Anabolic Steroids

  • First exemptions ever approved in the 1980s (before known as TUEs).

  • Used for the treatment of hypogonadism (low testosterone production).

  • Doctors could prescribe testosterone to treat low serum testosterone levels (Fitch, 2012).

Insulin

  • Allowed for those with type I diabetes (insulin-dependent diabetes mellitus).

  • Insulin is anabolic, providing a greater capacity to build muscle.

  • Use is estimated to be around 1/1000 – 1/1500 athletes (Fitch, 2012).

Beta-2 Agonists

  • Drugs used primarily to treat asthma.

  • Can be taken before exercise to prevent exercise-induced bronchoconstriction.

  • Can be taken after the onset of symptoms for relief.

  • Asthmatics are advised these should be used infrequently, typically less than twice a week.

Short-Acting vs. Long-Acting Beta-2 Agonists

  • Short-acting beta-2 agonists (SABAs) = acute relief, e.g., salbutamol (albuterol).

  • Long-acting beta-2 agonists (LABAs) = taken daily as a preventer to relax airway muscles, e.g., formoterol.

  • LABAs are used in combination with corticosteroids such as in Symbicort: formoterol (LABA) + budenoside (corticosteroid).

Mechanism of Action of Beta-2 Agonists

  • Act as ligands to adrenergic receptors (highly selective for beta-2 receptors).

  • Activates a transmembrane signal cascade through adenylyl cyclase.

  • Reduces Ca2+Ca^{2+} sensitivity, inhibits myosin light chain phosphorylation, and prevents muscle contraction (Tashkin & Fabbri, 2010).

Effects of Beta-2 Agonists

  • Metabolism.

  • Cardiac chronotropy and inotropy.

  • Lipolysis in adipose tissue.

  • Hepatic glucose production and release.

  • Pancreatic production and secretion of insulin.

  • Muscle growth

  • Adrenal production and secretion of epinephrine.

  • Ca2+Ca^{2+} cycling.

  • K+K^{+} transport.

  • Substrate cycling.

  • Protein turnover.

Anabolic and Lipolytic Actions of Beta-2 Agonists

  • High relative systemic bioavailability even if inhaled.

  • Beta-2 agonists have anabolic and lipolytic effects.

  • Elicit muscle hypertrophy, increase strength, and reduce fat mass.

  • Used in the feeding of some livestock to increase the efficiency of meat production (Hostrup et al., 2020).

Beta Agonists and Muscle Anabolism

  • Salbutamol increases muscle protein turnover.

  • Stimulates MPS (Muscle Protein Synthesis) after resistance exercise.

  • Augments hypertrophy of a resistance exercise program.

  • 4 weeks of terbutaline (5mg/30kg BM twice daily) increases lean mass by 1.7kg (Hostrup et al., 2015, 2018; Caruso et al., 2005).

Beta Agonists and Fat Metabolism

  • Salbutamol increases resting metabolic rate.

  • Increases fat oxidation.

  • Increases lipolysis.

  • Good for fatty acid partitioning, i.e., promotes leanness.

  • 4 weeks terbutaline (5mg/30kg BM twice daily) promotes loss of 1.4kg fat mass (Hostrup et al., 2015; Vaisman et al., 1987; Hoeks et al., 2003; Gaugg et al., 2017).

Athlete use

  • Clenbuterol and terbutaline are the most common adverse findings (Hostrup et al., 2020).

Famous Cases

  • Canelo Alvarez tested positive for traces of clenbuterol, attributed to contaminated meat.

Athlete Dosing Regimens

  • Clenbuterol: Progressive increase from 40 to 120 μ\mug.

  • Salbutamol/albuterol: Progressive increase from 4 mg twice daily to 8 mg three times daily.

Purported strategies

  • 2 weeks on, 2 weeks off: Starting at a low dose and increasing progressively to a maximum dose.

  • Continuous use: Starting at a low dose and increasing the dose every 2-3 weeks until the maximum dose is reached.

  • Short-term use: Starting at a low dose and increasing the dose 1-2 times per week, reaching a maximum dose maintained for 7-14 days. Total duration of 4-6 weeks. Discontinue for 4-6 weeks before repeating.

  • Beta2-agonist administration is limited to a maximum of 16 weeks per year to reduce side effects.

Corticosteroids

  • Anti-inflammatory medication.

  • Used in the treatment of asthma and COPD.

  • Can be used for painful joints, e.g., in arthritis.

  • Used to treat inflammatory bowel disease such as Crohn’s.

Mechanism of Action of Corticosteroids

  • Mimic hormones naturally produced by the adrenal gland (hydrocortisone and cortisone).

  • Reduce swelling and inflammation.

  • Also reduce the activity of the immune system.

  • Two types:

    • Glucocorticoids: Suppress inflammation and immunity.

    • Mineralocorticoids: Regulate the balance of salt and water.

Types of Corticosteroids

  • Synthetic corticosteroids used for adrenal insufficiency (e.g., Addison’s disease).

  • Main ones used in TUEs:

    • Prednisone

    • Prednisolone

    • Triamcinolone

    • Dexamethasone

Corticosteroids Mechanism of Action

  • Decreases inflammatory cells (Eosinophil, T-lymphocyte, Macrophage, Dendritic cell)

  • Decreases structural cells (Epithelial cell, Endothelial cell, Airway smooth muscle, Mucus gland)

  • Decreases Cytokines and Mediators (Barnes, 2010).

Prednisolone and Performance

  • 10 male athletes performed two cycling trials at 70-75% VO2max until exhaustion.

  • Received either placebo (lactose) or Prednisolone 60mg/d for 1 week.

  • Time to exhaustion increased with Prednisolone: 75 vs. 46 mins.

  • Glucose and insulin were higher with prednisolone.

  • Blood lactate was higher with prednisolone (Arlettaz et al., 2007).

Summary

  • Beta-2-agonists and corticosteroids are two common medicines where TUE is requested.

  • No such thing as side effects; in this instance, “side effects” can be performance-enhancing.

  • Potent performance-enhancing effects of some drugs.

  • Benefits to physiology are not confined to what the drug is designed to treat!